Alcohol and postmenopausal hormone use are well-established modifiable risk factors for breast cancer. Alcohol may decrease the metabolic clearance of estradiol, whereby the risk of breast cancer associated with hormone use may depend on blood alcohol levels. The objective is to determine whether alcohol interacts with hormone use on risk of breast cancer. The 5,035 postmenopausal women who participated in the Copenhagen City Heart Study were asked about their alcohol intake and hormone use at baseline in 1981–1983 and were followed until 2002 in the Danish cancer registry, with <0.1% loss to follow-up. Proportional hazard models were used to analyze data. During follow-up, 267 women developed breast cancer. Alcohol consumption was associated with a small increased risk of breast cancer (hazard ratio = 1.11 per drink/day, 95% CI: 0.99–1.25). Women who used hormones also had a higher risk of breast cancer (HR = 2.00, 95% CI: 1.52–2.61) compared to nonhormone users. We found an interaction between these 2 factors; those who had an intake of more than 2 drinks per day and took hormones had a risk of 4.74 (95% CI: 2.61–8.59) for breast cancer compared to abstainers who did not use hormones. Alcohol was not associated with breast cancer among women who did not use hormones (HR = 0.98 per drink/day, 95% CI: 0.82–1.78). In conclusion, the interaction between alcohol and hormone use should, if confirmed in other studies, have an impact both on the prescription of hormones and on sensible drinking limits for postmenopausal women. © 2007 Wiley-Liss, Inc.